Tetraenyl prostanoic acid derivatives as prodrugs for the treatment of peptic ulcer disease

ABSTRACT

Tetraenyl Prostanoic Acid derivatives which are useful as prodrugs for the treatment of peptic ulcer disease and are represented by the following general formula ##STR1## are disclosed.

BACKGROUND OF THE INVENTION

This invention relates to a novel class of prostanoic acid derivatives,to a method of treating peptic ulcer disease, and to pharmaceuticalcompositions containing these derivatives.

It is known that certain prostaglandins have been found to be useful inthe treatment of peptic ulcer disease. It is further known that aspecific class of these prostaglandins, namely tetraenyl, 16-hydroxyprostaglandins which are represented by the following structural formula##STR2## wherein R represents hydrogen or lower alkyl having 1 to 6carbon atoms; R₁ represents vinyl, or lower alkyl having 1 to 4 carbonatoms and the wavy line represents R or S stereochemistry; R₂, R₃ and R₄are hydrogen or lower alkyl having 1 to 4 carbon atoms or R₂ and R₃together with carbon Y form a cycloalkenyl having 4 to 6 carbon atoms orR₃ and R₄ together with carbons X and Y form a cycloalkenyl having 4 to6 carbons have potent gastric antisecretory and cytoprotectiveproperties which makes them effective in the treatment of peptic ulcerdisease. These compounds are described further in U.S. Pat. No.4,683,328.

Applicants have discovered that certain 16-alkyl tetraenyl prostanoicacid derivatives which are represented by formula I function as in vivoprecursors or pro drugs of the aforementioned 16-hydroxy tetraenylprostanoic acid derivatives which are represented by formula IV (SchemeA). In order for the compounds of formula I to exert their antisecretoryand cytoprotective properties they must be "transformed" into the activespecies which are represented by formula IV. This "transformation" takesplace in an acidic medium. Thus the pro drugs must be administered by amethod that would allow for exposure to said condition.

Detailed Description of the Invention

The specific prodrugs of this invention are the compounds represented bythe following structural formula ##STR3## or a pharmaceuticallyacceptable base addition salt when R is hydrogen thereof:

wherein R is hydrogen or alkyl having I to 6 carbon atoms; R₁ is alkylhaving 1 to 6 carbon atoms; R₂, R₃ and R₄ are each independentlyhydrogen or alkyl having 1 to 4 carbon atoms or R₃ and R₄ together withcarbons X and Y form a cycloalkyl having 4 to 6 carbon atoms or acycloalkenyl having 4 to 6 carbon atoms with the proviso that thecycloalkenyl group is only present when A is present; A is an optionallypresent alkoxy group having 1 to 6 carbon atoms with the proviso thatwhen A is present the double bond at carbon 16 and carbon 18 of formulaI shifts to carbon 17 and carbon 19, respectively; B is an optionallypresent group represented by the following formula

    OR.sub.5

wherein R₅ is hydrogen, alkyl having 1 to 4 carbon atoms or acyl whichis represented by the following formula ##STR4## wherein R₆ is alkylhaving 1 to 6 carbon atoms with the proviso that B is present when A isnot present.

A preferred embodiment of the present invention are compounds of theformula ##STR5## wherein R is alkyl having 1 to 6 carbon atoms; R₁ isalkyl having 1 to 6 carbon atoms; R₂ is hydrogen; R₃ and R₄ togetherwith carbon X and Y form a cycloalkyl having 4 to 6 carbon atoms; R₅ ishydrogen, alkyl having 1 to 4 carbon atoms or acyl which is representedby the following formula ##STR6## wherein R₆ is alkyl having 1 to 6carbon atoms. Exemplifying this embodiment are the following compounds

(±)-methyl7-[3α-hydroxy-2β-[6-(2-hydroxy-Z-cyclopentylidine)-4-methyl-1E,4E-hexadienyl]-5-oxo-1α-cyclopentyl]-4Z-heptenoateand

(±)-methyl7-[2β-(6-(2-(acetyloxy)-Z-cyclopentylidine]-4-methyl-1E,4E-hexadienyl]-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate

Another preferred embodiment of the present invention are compounds ofthe formula ##STR7## wherein R is alkyl having 1 to 6 carbon atoms; R₁is alkyl having 1 to 6 carbon atoms; R₂, R₃ and R₄ are eachindependently hydrogen or alkyl having 1 to 4 carbon atoms; and R₅ ishydrogen, alkyl having 1 to 4 carbon atoms or acyl which is representedby the following formula ##STR8## wherein R₆ is alkyl having 1 to 6carbon atoms.

Exemplifying this embodiment are the following compounds

(±)-methyl 7-[3α-hydroxy-2β-(8-hydroxy-4,8-dimethyl-1E,4,6-nonatrienyl)-5-oxo-1α-cyclopentyl]-4Z-heptenoateand

(±)-methyl 7-[3α-hydroxy-2β-(8-methoxy-4,8-dimethyl-1E,4,6-nonatrienyl)-5-oxo-1α-cyclopentyl]-4Z-heptenoate

A further preferred embodiment of the present invention are compounds ofthe formula ##STR9## wherein R is alkyl having 1 to 6 carbon atoms; R₁is alkyl having 1 to 6 carbon atoms; R₂, R₃ and R₄ are eachindependently hydrogen or alkyl having 1 to 4 carbon atoms; and R₇ isalkyl having 1 to 6 carbon atoms.

Exemplifying this embodiment is the following compound

(±)-methyl7-[2β-(4,8-dimethyl-4-methoxy-1E,5E,7E-nonatrienyl)-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate

As used herein the term "alkyl having 1 to 6 carbon atoms" refers tostraight chain or branched chain hydrocarbon groups having from one tosix carbon atoms. Illustrative of such alkyl groups are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl andisohexyl.

As used herein the term "cycloalkyl having from 4 to 6 carbon atoms"included cycloalkyl groups having from four to six carbon atoms.Illustrative of such cycloalkyl groups are cyclobutyl, cyclopentyl andcyclohexyl.

As used herein the term "cycloalkenyl having 4 to 6 carbon atoms"included cycloalkenyl groups having from four to six carbon atoms.Illustrative of such cycloalkenyl groups are cyclobutenyl, cyclopentenyland cyclohexenyl.

As used herein the term "alkoxy wherein the alkyl is 1 to 6 carbonatoms" refers to straight or branched chain ethers. Illustrative of suchgroups are methoxy, ethoxy, propoxy, butoxy, isopropoxy and the like.

Compounds of general Formula I can possess one or more asymmetric carbonatoms and are thus capable of existing in the form of optical isomers aswell as in the form of racemic or diastereoisomeric mixtures thereof.The optical isomers and mixtures thereof can be obtained by processesdescribed in U.S. Pat. Nos. 4,683,328 and 4,863,961, by formation andchromatographic separation of diastereoisomeric derivatives and thenregeneration of the resolved product.

Within this class of prostaglandin, compounds and derivatives of theinvention are the pharmaceutically-acceptable salts of the compounds ofFormula I when R=H. The term "pharmaceutically-acceptable salts"embraces salts commonly used to form alkali metal salts. The nature ofthe salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable baseaddition salts of compounds of Formula I include alkali metal salts,e.g., salts of sodium and potassium, and ammonium salts and amine salts.All of these salts may be prepared by conventional means from thecorresponding compound of Formula I by reacting, for example, theappropriate base with the compound of Formula I.

The compounds of formula (I) may be prepared in accordance with thefollowing procedures: ##STR10## wherein R, R₁, R₂, R₃, R₄ and R₅ aredefined as before. This general reaction as well as specificpreparations of compounds encompassed by Formula IV are described inU.S. Pat. No. 4,683,328. Compounds of formula IV will undergo acidcatalyzed allylic rearrangement to give the compounds of formula II:##STR11## wherein R, R₁, R₂, R₃, R₄, R₅ and R₇ are defined as before.Scheme B follows the Scheme A synthetic route to the preparation of thedi-silylated precursors of Formula IV, Scheme A. The di-silylatedintermediates are then treated with pyridinium p-toluenesulfonate togive the compounds of Formula II and Formula III which are separated bychromatographic methods.

This invention also relates to a method of treatment for subjectssuffering from peptic ulcer disease, and more specifically, a method oftreatment involving the administration of compounds which arerepresented by formula I as the active ingredient. The compounds of thepresent invention must be administered by an oral route, preferably inthe form of a pharmaceutical composition adapted to such a route, and ina dose effective for the treatment intended. Therapeutically effectivedoses of the compounds of the present invention required to prevent orarrest the progress of the medical condition are readily ascertained byone of ordinary skill in the art.

Accordingly, the invention provides a class of novel pharmaceuticalcompositions comprising one or more compounds of the present inventionin association with one or more nontoxic, pharmaceutically acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as "carrier" materials) and if desired other active ingredients.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit contained in a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. These may with advantagecontain an amount of active ingredient from about 1 to 500 μg,preferably from about 5 to 200 μg. A suitable daily dose for a subjectmay vary widely depending on the condition of the patient and otherfactors. However, a dose of from about 0.01 to 1000 ug/kg body weight,particularly from about 0.1 to 100 ug/kg body weight may be appropriate.

For therapeutic purposes, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate to the indicated routeof administration. For per os administration, the compounds may beadmixed with lactose, sucrose, starch power, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulphuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol, and thus tableted or encapsulated forconvenient administration.

Alternatively, the compounds may be dissolved in water, polyethyleneglycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil,sesame oil, benzyl alcohol, sodium chloride, and/or various buffers..Other adjuvants are well and widely known in the pharmaceutical art.Appropriate dosages, in any given instance, of course depend upon thenature and severity of the condition treated and the species of mammalinvolved, including its size and any individual idiosyncrasies.

Representative carriers, diluents and adjuvants include for example,water, lactose, gelatin, starches, magnesium stearate, talc, vegetableoils, gums, polyalkylene glycols, petroleum jelly, etc. Thepharmaceutical compositions may be made up in a solid form such asgranules or powders or in a liquid form such as solutions, suspensionsor emulsions. The pharmaceutical compositions may be subjected toconventional pharmaceutical operations such as sterilization and/or maycontain conventional pharmaceutical adjuvants such as preservatives,stabilizers, wetting agents, emulsifiers, buffers, etc.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated. For example, a formulation intended for the oraladministration of subjects may contain from 1 μg to 500 μg of activeagent compounded with an appropriate and convenient amount of carriermaterial which may vary from about 5 to 95 percent of the totalcomposition. Dosage unit forms will generally contain between from about1 μg to about 500 μg of active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, rate of excretion,drug combination and the severity of the particular disease undergoingtherapy.

The following Examples are intended to further illustrate the presentinvention and not to limit the invention in spirit or scope.

EXAMPLE 1 Preparation of (±)-methyl7-[3α-hydroxy-2β-(6-(2-hydroxy-Z-cyclopentylidine)-4-methyl-1E,4E-hexadienyl]-5-oxo-1α-cyclopentyl]-4Z-heptenoate##STR12##

The di-silylated intermediate (±)-methyl7-[2β-(6-(1-cyclopenten-1-yl)-4-methyl-4-[trimethylsilyl)oxy]-1E,5E-hexadienyl]-5-oxo-3α-[(triethylsilyl)-1α-cyclopentyl]-4Z-heptenoate(830 mg) was dissolved in a mixture of 18 ml of acetone and 2 ml H₂ Oand 26 mg of pyridinium p-toluenesulfonate (PPTS) was added. Thesolution was allowed to stand at room temperature for about 24 hours.The solution was reduced in volume on a rotary evaporator and theresulting mixture was diluted with ether and washed with water and thensaturated sodium chloride solution. The organic layer was dried oversodium sulfate (Na₂ SO₄) and evaporated on a rotary evaporator. Theresidue was chromatographed on silica gel with 70% ethyl acetate/30%hexane as eluent to give 15 mg of the title compound and 120 mg of amixture of deprotected starting material.

NMR data for title compound: ¹ H (CDCl₃) δ1.77 (s,C-16 CH₃); 2.24, 2.75(multiplets C-10 H's); 2.86 (d C-15 H's); 4.49 (broad, s,C-20 H); 6.37(d, C-17 H); 5.92 (d, C-18 H). This compound is a mixture of eightisomers at C-16 (E and Z), C-18 (E and Z) and C-20 (R and S).

EXAMPLE 2 Preparation of (±)-methyl7-[3α-hydroxy-2β-(6-(2-hydroxy-Z-cyclopentylidine)-4-methyl-1E,4E-hexadienyl]-5 oxo-1α-cyclopentyl]-4Z-heptenoate ##STR13## AlternateMethod

(±)-methyl7-[2β-(6-(1-cyclopenten-1-yl)-4S-hydroxy-4-methyl-1E,5E-hexadienyl]-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate(100 mg) dissolved in 2 ml THF was added in one portion to 15 ml offresh dog gastric juice (pH˜1) with stirring. The turbid mixture wasstirred for 1 hour at room temperature. The mixture was extracted withether and then twice with ethyl acetate. The organic extracts werecombined, washed with H₂ O and then saturated sodium chloride solution,dried (Na₂ SO₄) and evaporated. The residue was chromatographed onsilica gel using 55% ethyl acetate/45% hexane as eluent to give 3.4 mgof the title compound and a mixture of (±)-methyl7-[2β-(6-(1-cyclopenten-1-yl)-4R-hydroxy-4-methyl-1E,5E-hexadienyl]-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate and(±)-methyl7-[2β(6-(1-cyclopenten-1-yl)-4S-hydroxy-4-methyl-1E,5E-hexadienyl]-3.alpha.-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate.

NMR data for title compound: ¹ H (CDCl₃) δ1.77 (s,C-16 CH3); 2.24, 2.75(multiplets C-10 H's); 2.86 (d C-15 H's); 4.49 (broad, s,C-20 H); 6.37(d, C-17 H); 5.92 (d, C-18 H). This compound is a mixture of eightisomers at C-16 (E and Z), C-18 (E and Z) and C-20 (R and S).

EXAMPLE 3 Preparation of (±)-methyl 7-[3α-hydroxy-2β-(8-methoxy-4,8-dimethyl-1E,4,6-nonatrienyl)-5-oxo-1α-cyclopentyl]-4Z-heptenoate##STR14## and (±)-methyl7-[2α-(4,8-dimethyl-4-methoxy-1E,5E-7E-nonatrienyl)-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate##STR15##

A solution of 92 mg of the disilylated prostaglandin in 4 ml of methanoland several crystals of pyridinium p-toluenesulfonate was allowed tostand at room temperature for 3 hours. The solution was reduced involume on a rotary evaporator, diluted with ether and washed twice withH₂ O, once with saturated NaCl solution, dried (Na₂ SO₄) and evaporated.Chromatography of the residue on silica gel with 50% ethyl acetate/50%hexane as eluent gave 13 mg of (±)-methyl7-[3α-hydroxy-2β-(8-methoxy-4,8-dimethyl-1E,4,6-nonatrienyl)-5-oxo-1α-cyclopentyl]-4Z-heptenoate

NMR: ¹ H (CDCl₃) δ1.21 (s,C-20 CH₃); 3.18 (s,C-20 OCH₃); 2.24, 2.76(m,C-10 H's); 1.79 (s,C-16 CH₃); 5.89 (d, C-17 H); 6.37 (dd, C-18 H);5.59 (d, C-19 H). This compound is an approximate 3:2 mixture of E and Zisomers at C-16.

and 9.1 mg of (±)-methyl7-[2β-(4,8-dimethyl-4-methoxy-1E,5E,7E-nonatrienyl)-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate

NMR: ¹ H (CDCl₃) δ1.28 (s,C-16 CH₃); 1.78, 1.79 (s,C-20 CH₃); 3.17(s,C-16 OCH₃); 5.45, 5.46 (m,C-17 H); 5.84 (d,C-19 H); 6.34, 6.35(m,C-18 H).

EXAMPLE 4 Preparation of (±)-methyl7-[3α-hydroxy-2β-(8-hydroxy-4,8-dimethyl-1E,4,6-nonatrienyl)-5-oxo-1α-cyclopentyl]-4Z-heptenoate##STR16##

A mixture of (±)-methyl7-[2β-(4,8-dimethyl-4R-hydroxy-1E,5E,7E-nonatrienyl)-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoateand (±)-methyl7-[2β-(4,8-dimethyl-4S-hydroxy-1E,5E,7E-nonatrienyl)-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate(90 mg) was dissolved in a mixture of 6 ml of acetone and 2 drops of 0.5N HCl and allowed to stand at room temperature for 3 hours. The solutionwas diluted with ether and washed successively with dilute NaHCO₃solution and saturated NaCl solution and evaporated. The residue waschromatographed with 65% ethyl acetate/35% hexane as eluent to give 17mg of the title compound.

NMR: ¹ H(CDCl₃) δ1.35 (s,C-20 CH₃); 1.77 (s,C-16 CH₃); 5.77 (m,C-19 H);5.86 (m,C-17 H); 5.95 (m,C-18 H).

EXAMPLE 5 Preparation of (±)-methyl7-[2β-(6-(2-(acetyloxy)-Z-cyclopentylidine]-4-methyl-1E,4E-hexadienyl]-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate##STR17##

(±)-methyl7-[2β-(6-(1-cyclopenten-1-yl)-4S-hydroxy-4-methyl-1E,5E-hexadienyl]-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate(0.13 g) was mixed with 3 ml glacial acetic acid at room temperature andstirred under N₂ for 24 hours. The reaction was quenched by addition to50 ml saturated NaHCO₃ solution and was extracted with 2 portions ofethyl ether. The combined ether extracts were washed with brine, anddried (Na₂ SO₄) Chromatography on silica (45% Ethyl acetate/55% Hexane)gave 52 mg of the title compound.

NMR: ¹ H (CDCl₃) δ2.06 (s,acetyl CH₃); 1.77 (s,C-16 CH₃); 5.49, 5.53(m,C-20 H); 5.90, 5.94 (d,C-18 H); 6.41, 6.47 (d,C-17 H). This compoundis an approximate 4:1 mixture of isomers, probably C-20 R and Sdiastereomers.

EXAMPLE 6

In vitro regeneration of 16-hydroxy compounds A and B from correspondingprodrug.

(±)-methyl7-[2β-(4,8-dimethyl-4R-hydroxy-1E,5E,7E-nonatrienyl)-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate##STR18## and

(±)-methyl7-[2β-(4,8-dimethyl-4S-hydroxy-1E,5E,7E-nonatrienyl)-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate##STR19##

5 mg of the product of Example 4 was dissolved in 1 ml of a 3:1:1mixture of acetic acid, THF (tetrahydrofuran) and H₂ O and allowed tostand about 1 hour at room temperature. Thin layer monitoring withstandards of Compounds A and B indicated the generation of the titlecompounds and the diminishment of starting material.

EXAMPLE 7

(±)-Methyl7-[3α-hydroxy-2β-[6-(2-hydroxy-Z-cyclopentylidine)-4-methyl-1E,4E-hexadienyl]-5-oxo-1α-cyclopentyl]-4Z-heptenoate(Compound of Example 1),

(±)-methyl7-[3α-hydroxy-2β-(8-hydroxy-4,8-dimethyl-1E,4,6-nonatrienyl-5-oxo-1α-cyclopentyl]-4Z-heptenoate(Compound of Example 4), and

(±)-methyl7-[2β-[6-(2-(acetyloxy)-Z-cyclopentylidine)-4-methyl-1E,4E-hexadienyl]-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate(Compound of Example 5) were tested for gastric antisecretory activityin the Pavlov Pouch Dog Test. The procedure for this test is describedas follows.

Adult female beagles (6-11 kg), with innervated (Pavlov) gastricpouches, were food deprived with access to water 24 h prior toexperiments. Following a 30 min basal collection period, theprostaglandin in a buffer/ethanol vehicle was administered into thepouch through a Thomas cannula followed by either a saline or 0.1N HClflush. Thirty minutes later the gastric pouch was emptied and gastricsecretion was stimulated by feeding 10-12 oz of canned dog food(Evanger's Dog and Cat Food Co., Inc., Wheeling, Ill.). Gastric juicesamples were collected over a 4 h period at 30 min intervals. Total acidoutput (mequiv/30 min) was determined for each collection period bymultiplying the volume of secretion (mL/30 min) and the acidity(mequiv/L). Percent reduction of total acid output from control wascalculated over each 4 h experiment.

The compounds of Example 1, 4 and 5, have the following results:

    ______________________________________                                                                          % Decrease in                                                                 4 hr Total                                  Compound of                                                                             n     Flush     Dose    Acid Output                                 ______________________________________                                        Example 1 4     saline    0.3 μg/kg                                                                          31                                                    2     0.1 NHCl  0.3 μg/kg                                                                          87                                          Example 4 2     saline    0.3 μg/kg                                                                          28                                                    2     0.1 NHCl  0.3 μg/kg                                                                          76                                          Example 5 2     saline    0.3 μg/kg                                                                          88                                                    2     0.1 NHCl  0.3 μg/kg                                                                          73                                          ______________________________________                                    

What we claim is:
 1. A compound of the general formula: ##STR20## or apharmaceutically acceptable base addition salt when R is hydrogenthereof:wherein R is hydrogen or alkyl having 1 to 6 carbon atoms; R₁ isalkyl having 1 to 6 carbon atoms; R₂, R₃ and R₄ are each independentlyhydrogen or alkyl having 1 to 4 carbon atoms or R₃ and R₄ together withcarbons X and Y form a cycloalkyl having 4 to 6 carbon atoms; wherein R₅is hydrogen, alkyl having 1 to 4 carbon atoms or acyl which isrepresented by the following formula ##STR21## wherein R₆ is alkylhaving 1 to 6 carbon atoms.
 2. A compound of claim 1 having thefollowing formula ##STR22## wherein R is alkyl having 1 to 6 carbonatoms; R₁ is alkyl having 1 to 6 carbon atoms; R₂ is hydrogen; R₃ and R₄together with carbon X and Y form a cycloalkyl having 4 to 6 carbonatoms; R₅ is hydrogen, alkyl having 1 to 4 carbon atoms or acyl which isrepresented by the following formula ##STR23## wherein R₆ is alkylhaving 1 to 6 carbon atoms.
 3. A compound of claim 2 which is(±)-methyl7-[2β-(6-(2-(acetyloxy)-Z-cyclopentylidine]-4-methyl-1E,4E-hexadienyl]-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate.4. A compound of claim 2 which is(±)-methyl7-[3α-hydroxy-2β-(6-(2-hydroxy-Z-cyclopentylidine]-4-methyl-1E,4E-hexadienyl]-5-oxo-1α-cyclopentyl]-4Z-heptenoate.5. A compound of claim 1 having the following formula ##STR24## whereinR is alkyl having 1 to 6 carbon atoms; R₁ is alkyl having 1 to 6 carbonatoms; R₂, R₃ and R₄ are each independently hydrogen or alkyl having 1to 4 carbon atoms; and R₅ is hydrogen, alkyl having 1 to 4 carbon atomsor acyl which is represented by the following formula ##STR25## whereinR₆ is alkyl having 1 to 6 carbon atoms.
 6. A compound of claim 5 whichis(±)-methyl7-[3α-hydroxy-2β-(8-hydroxy-4,8-dimethyl-1E,4,6-nonatrienyl)-5-oxo-1α-cyclopentyl]-4Z-heptenoate.7. A compound of claim 5 which is(±)-methyl7-[3α-hydroxy-2β-(8-methoxy-4,8-dimethyl-1E,4,6-nonatrienyl)-5-oxo-1α-cyclopentyl]-4Z-heptenoate.8. A pharmaceutical composition useful for treating peptic ulcer diseasein mammals comprising at least one compound according to claim 1,together with one or more non-toxic pharmaceutically acceptablecarriers.
 9. A pharmaceutical composition according to claim 8 whereinsaid compound is selected from the group consisting of(±)-methyl7-[3α-hydroxy-2β-(8-hydroxy-4,8-dimethyl-1E,4,6-nonatrienyl)-5-oxo-1α-cyclopentyl]-4Z-heptenoate,(±)-methyl7-[3α-hydroxy-2β-(8-methoxy-4,8-dimethyl-1E,4,6-nonatrienyl)-5-oxo-1α-cyclopentyl]-4Z-heptenoate,(±)-methyl7-[3α-hydroxy-2β-(6-(2-hydroxy-Z-cyclopentylidine]-4-methyl-1E,4E-hexadienyl]-5-oxo-1α-cyclopentyl]-4Z-heptenoate,and (±)-methyl7-[2β-(2-(acetyloxy)-Z-cyclopentylidine]-4-methyl-1E,4E-hexadienyl]-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate.10. A method for treating peptic ulcer disease in mammals comprisingadministering a therapeutically effective dose of at least one compoundof claim 1 to a mammal in need of such treatment.
 11. A method accordingto claim 10 wherein said compound is selected from the group consistingof(±)-methyl7-[3α-hydroxy-2β-(8-hydroxy-4,8-dimethyl-1E,4,6-nonatrienyl)-5-oxo-1α-cyclopentyl]-4Z-heptenoate,(±)-methyl7-[3α-hydroxy-2β-(8-methoxy-4,8-dimethyl-1E,4,6-nonatrienyl)-5-oxo-1α-cyclopentyl]-4Z-heptenoate,(±)-methyl7-[3α-hydroxy-2β-(6-(2-hydroxy-Z-cyclopentylidine]-4-methyl-1E,4E-hexadienyl]-5-oxo-1α-cyclopentyl]-4Z-heptenoate,and (±)-methyl7-[2β-(6-(2-(acetyloxy)-Z-cyclopentylidine]-4-methyl-1E,4E-hexadienyl]-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate.